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Protein Phosphatase 2A Inhibiting β-Catenin Phosphorylation Contributes Critically to the Anti-renal Interstitial Fibrotic Effect of Norcantharidin

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Abstract

Norcantharidin (NCTD) is a potential anti-renal interstitial fibrotic drug. However, the underlying molecular mechanism of how NCTD works remains unclear. In this study, using both in vivo and in vitro models, we report that the level of β-catenin is positively correlated to the degree of renal interstitial fibrosis (RIF). Protein phosphatase 2A (PP2A) binds to β-catenin and suppresses its phosphorylation, thereby increasing the total β-catenin expression. Additionally, NCTD dramatically elevates the level of phosphorylated β-catenin and decreases total β-catenin expression in a dose-dependent manner, consequently leading to the reduction of RIF. Mechanistically, PP2A-mediated suppression of β-catenin phosphorylation is an essential target for the anti-renal interstitial fibrotic effect of NCTD. Therefore, we report a potential theoretical basis for clinical application of NCTD in treating RIF.

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Abbreviations

NCTD:

Norcantharidin

RIF:

Renal interstitial fibrosis

PP2A:

Protein phosphatase 2A

UUO:

Unilateral ureter obstruction

HK-2 cells:

Human proximal tubular cells

Col-I:

Collagen type I

CKD:

Chronic kidney disease

TGF-β1:

Transforming growth factor-beta1

OA:

Okadaic acid

ECM:

Extracellular matrix

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Acknowledgments

This study was supported by the Natural Science Foundation of China (Grant No. 81100486 and 81370792), the Hunan Provincial Science and Technology Program of China (Grant No. 2017SK2072), and the Changsha Science and Technology Program of China (Grant No. kq1901122).

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Authors and Affiliations

  1. Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification in Hunan, the Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China

    Zheng Xiao, Lu Wen, Dong Zeng, Dandan Yin, Xun Zhou, Chengyuan Tang & Ying Li

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  1. Zheng Xiao
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  7. Ying Li
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Contributions

Zheng Xiao, Lu Wen, and Ying Li designed the experiments. Zheng Xiao wrote the manuscript. Ying Li provided the experimental materials. Zheng Xiao and Dong Zeng performed the experiments. Zheng Xiao, Lu Wen, and Dandan Yin performed the data analysis. Xun Zhou and Chengyuan Tang revised and put valuable inputs in the manuscript.

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Correspondence to Ying Li.

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Xiao, Z., Wen, L., Zeng, D. et al. Protein Phosphatase 2A Inhibiting β-Catenin Phosphorylation Contributes Critically to the Anti-renal Interstitial Fibrotic Effect of Norcantharidin. Inflammation 43, 878–891 (2020). https://doi.org/10.1007/s10753-019-01173-0

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